Diabetes is classified as either type 1 (early onset) or type 2 (adult onset), with type 2 comprising 90-95% of the cases of diabetes. Diabetes is the final stage in a disease process that begins to affect individuals long before the diagnosis of diabetes is made. Type 2 diabetes develops over 10 to 20 years and results from an impaired ability to utilize glucose (glucose utilization, glucose uptake in peripheral tissues) due to impaired sensitivity to insulin (insulin resistance).
Moreover, insulin resistance is central to development of a number of different diseases and conditions, such as nonalcoholic steatohepatitis (NASH), polycystic ovary syndrome (PCOS), cardiovascular disease, metabolic syndrome, and hypertension.
In pre-diabetes, insulin becomes less effective at helping tissues metabolize glucose. Pre-diabetics may be detectable as early as 20 years before diabetic symptoms become evident. Studies have shown that although patients show very few overt symptoms, long-term physiological damage is already occurring at this stage. Up to 60% of these individuals will progress to type 2 diabetes within 10 years.
The American Diabetes Association (ADA) has recommended routine screening to detect patients with pre-diabetes. Current screening methods for pre-diabetes include the fasting plasma glucose (FPG) test, the oral glucose tolerance test (OGTT), the fasting insulin test and the hyperinsulinemic euglycemic clamp (HI clamp). The first two tests are used clinically whereas the latter two tests are used extensively in research but rarely in the clinic. In addition, mathematical means (e.g., HOMA, QUICKI) that consider the fasting glucose and insulin levels together have been proposed. However, normal plasma insulin concentrations vary considerably between individuals as well as within an individual throughout the day. Further, these methods suffer from variability and methodological differences between laboratories and do not correlate rigorously with HI clamp studies.
Worldwide, an estimated 194 million adults have type 2 diabetes and this number is expected to increase to 333 million by 2025, largely due to the epidemic of obesity in westernized societies. In the United States, it is estimated that over 54 million adults are pre-diabetic. There are approximately 1.5 million new cases of type 2 diabetes a year in the United States. The annual US healthcare cost for diabetes is estimated at $174 billion. This figure has risen more than 32% since 2002. In industrialized countries such as the U.S., about 25% of medical expenditures treat glycemic control, 50% is associated with general medical care associated with diabetes, and the remaining 25% of the costs go to treat long-term complications, primarily cardiovascular disease. Considering the distribution of the healthcare costs and the fact that insulin resistance is a direct causal factor in cardiovascular disease and diabetes progression, it is no surprise that cardiovascular disease accounts for 70-80% of the mortality observed for diabetic patients. Detecting and preventing type 2 diabetes has become a major health care priority.
Diabetes may also lead to the development of other diseases or conditions, or is a risk factor in the development of conditions such as Metabolic Syndrome and cardiovascular diseases. Metabolic Syndrome is the clustering of a set of risk factors in an individual. According to the American Heart Association these risk factors include: abdominal obesity, decreased ability to properly process glucose (insulin resistance or glucose intolerance), dyslipidemia (high triglycerides, high LDL, low HDL cholesterol), hypertension, prothrombotic state (high fibrinogen or plasminogen activator inhibitor-1 in the blood) and proinflammatory state (elevated C-reactive protein in the blood). Metabolic Syndrome is also known as syndrome X, insulin resistance syndrome, obesity syndrome, dysmetabolic syndrome and Reaven's syndrome. Patients diagnosed with Metabolic Syndrome are at an increased risk of developing diabetes, cardiac and vascular disease. It is estimated that, in the United States, 20% of the adults (>50 million people) have metabolic syndrome. While it can affect anyone at any age, the incidence increases with increasing age and in individuals who are inactive, and significantly overweight, especially with excess abdominal fat.
Type 2 diabetes is the most common form of diabetes in the United States. According to the American Diabetes Foundation over 90% of the US diabetics suffer from Type 2 diabetes. Individuals with Type 2 diabetes have a combination of increased insulin resistance and decreased insulin secretion that combine to cause hyperglycemia. Most persons with Type 2 diabetes have Metabolic Syndrome.
The diagnosis for Metabolic Syndrome is based upon the clustering of three or more of the risk factors in an individual. A variety of medical organizations have definitions for the Metabolic Syndrome. The criteria proposed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), with minor modifications, are currently recommended and widely used in the United States.
The American Heart Association and the National Heart, Lung, and Blood Institute recommend that the metabolic syndrome be identified as the presence of three or more of these components: increased waist circumference (Men—equal to or greater than 40 inches (102 cm), Women—equal to or greater than 35 inches (88 cm); elevated triglycerides (equal to or greater than 150 mg/dL); reduced HDL (“good”) cholesterol (Men—less than 40 mg/dL, Women—less than 50 mg/dL); elevated blood pressure (equal to or greater than 130/85 mm Hg); elevated fasting glucose (equal to or greater than 100 mg/dL).
Type 2 diabetes develops slowly and often people first learn they have type 2 diabetes through blood tests done for another condition or as part of a routine exam. In some cases, type 2 diabetes may not be detected before damage to eyes, kidneys or other organs has occurred. A need exists for an objective, biochemical evaluation (e.g. lab test) that can be administered by a primary care provider to identify individuals that are at risk of developing Metabolic Syndrome or Type 2 diabetes.
Newer, more innovative molecular diagnostics that reflect the mechanisms of the patho-physiological progression, including assessing and monitoring functional beta-cell mass, to pre-diabetes and diabetes are needed because the prevalence of pre-diabetes and diabetes is increasing in global epidemic proportions. Mirroring the obesity epidemic, pre-diabetes and diabetes are largely preventable but are frequently undiagnosed or diagnosed too late due to the asymptomatic nature of the progression to clinical disease. As the disease progresses beta-cell function diminishes.
Although insulin resistance plays a central role in the development of numerous diseases, it is not readily detectable using many of the clinical measurements for pre-diabetic conditions. Insulin resistance develops prior to the onset of hyperglycemia and is associated with increased production of insulin. Over time (decades) the ability of the cell to respond to insulin decreases and the subject becomes resistant to the action of insulin (i.e., insulin resistant, IR). Eventually the beta-cells of the pancreas cannot produce sufficient insulin to compensate for the decreased insulin sensitivity and the beta-cells begin to lose function and apoptosis is triggered. Beta-cell function may be decreased as much as 80% in pre-diabetic subjects. As beta-cell dysfunction increases the production of insulin decreases resulting in lower insulin levels and high glucose levels in diabetic subjects. Vascular damage is associated with the increase in insulin resistance and the development of type 2 diabetes. The inability and, ultimately the failure, of pancreatic beta-cells to adapt the beta-cell mass (by activating beta-cell proliferation and differentiation, and inhibiting beta-cell apoptosis) to insulin demand eventually leads to a decrease in the functional beta-cell mass. Early detection of decreasing beta-cell function can facilitate earlier therapeutic intervention (drugs, lifestyle changes, etc) that will slow disease progression and, if intervention is sufficiently early, can restore functional beta-cell mass.
Current methods estimate the steady state beta-cell function as a percentage of a normal reference population. However, while the measures correspond well, they are not equivalent to non-steady state estimates of beta-cell function derived from stimulatory models such as the hyperinsulinaemic clamp, the hyperglycaemic clamp, the intravenous glucose tolerance test or the oral glucose tolerance test. Other methods have been developed using mathematical models to estimate beta cell function, such as the HOMA (Homeostasis Assessment Model). The equations, while widely used, are not appropriate for use with currently available insulin assays. Subsequently a quick and easy HOMA calculator was made available. While the HOMA calculator provides a quick and easy method for researchers wishing to use model-derived estimates of beta-cell function, it is still an indirect estimate that is insufficient to assess and monitor beta-cell function. Further, the development of therapeutic agents that facilitate the maintenance of functional beta-cell mass is needed to prevent and manage type 2 diabetes and related disorders.
Therefore there is an unmet need for diagnostic biomarkers and tests that can identify pancreatic beta-cell dysfunction and determine the risk of disease progression in subjects with impaired functional pancreatic beta-cell mass. Beta-cell function biomarkers and diagnostic tests can better identify and determine the risk of diabetes development in a pre-diabetic subject, can monitor disease development and progression and/or regression, can allow new therapeutic treatments to be developed and can be used to test therapeutic agents for efficacy on maintaining functional pancreatic beta-cell mass and thereby preventing or reversing type 2 diabetes and/or preventing related diseases. Further, a need exists for diagnostic biomarkers to more effectively assess the efficacy and safety of pre-diabetic and diabetic therapeutic candidates.